Angelman syndrome is a rare or orphan disease affecting an estimated 1 in 10,000-20,000 individuals globally. Diagnosed early during infancy, often before four years of age, Angelman syndrome is a neurodevelopmental disorder precipitated by the loss or abnormal function of E3 ubiquitin-protein ligase (UBE3A). Key hallmarks of the syndrome include intellectual disability, speech impediment, uncoordinated movements, and seizures.
In most cases, deletions in the maternal chromosome region 15q11-13, which affect the UBE3A allele, lead to Angelman phenotypes. Because paternal UBE3A expression is silent in neurons at birth, the absence or abnormal maternal protein virtually eliminates UBE3A function in the brain leading to neurodevelopmental deficits.
UBE3A has two principal biological functions, including ubiquitination and steroid hormone receptor activation. However, it’s not clear how exactly the loss of UBE3A function leads to the observed developmental deficits. In recent studies, investigators have taken advantage of an Angelman syndrome mouse model to dissect the biological basis for neurodevelopmental deficits. This mouse model recapitulates several key features of the human condition, including the cognitive deficit, motor dysfunction, and seizures. Therefore, investigators could connect the loss of UBE3A function with altered apoptosis and proliferation in the hippocampus. Specifically, loss of UBE3A activity led to decreased apoptosis (Simchi et al. 2020).
The relevance of this finding lies in the crucial role of apoptosis in the developing and adult brain. Programmed cell death pathways are involved in sculpting the brain by trimming cell numbers. These processes regulate the size of neural precursor, neuron, and glia populations and shape and ensure proper connectivity (Dekkers et al. 2013, Oppenheim, 1991, Ryu et al. 2016). Therefore, Simchi et al. suggested that due to the relevance of apoptotic and proliferative pathways in early brain development, strategies aiming to restore UBE3A expression in children would only partially rescue the condition.
Gene therapy strategies aim to restore the paternal UBE3A allele’s expression. To this end, investigators target a long non-coding antisense UBE3A transcript (UBE3A-ATS), which is responsible for the epigenetic silencing of the paternal UBE3A allele (Landers et al. 2004). For example, GeneTx Biotherapeutics LLC and Ultragenyx Pharmaceutical Inc. have developed an antisense RNA oligonucleotide, GTX-102, targeting UBE3A-ATS. They announced positive efficacy data as part of an interim Phase1/2 trial in five children. Positive outcomes included improvement in communication, behavior, sleep, and motor function. Unfortunately, serious adverse events were recorded at the highest doses involving leg weakness, which was related to an inflammatory response triggered by the investigational drug. Ultimately, although the adverse effects were observed in all participants, anti-inflammatory treatment resolved the mild to moderate reactions within weeks. Therefore, it seems that once dose reductions are implemented, the study will resume with additional safety and efficacy data due in 2021.
Lastly, findings from a recent preclinical study may provide a new alternative approach to Angelman syndrome treatment. Wolter et al. 2020 leveraged the strengths of the CRISPR/Cas9 system to target the UBE3A-ATS. They successfully identified guide RNAs (gRNA) targeting regions in or near Snord115 genes, which effectively led to the re-expression of the paternal UBE3A allele in mouse and human neurons. By packaging the identified gRNA and a small variant of Cas9 into an adeno-associated virus to treat embryonic mice, Wolter et al. were able to restore paternal UBE3A expression. This effect surprisingly persisted for 17 months due to the genome integration of the AAV vector. More importantly, the treatment prevented anatomical and behavioral phenotypes in Angelman syndrome model mice. Therefore, investigators are hopeful that such a strategy would prevent the typical neurodevelopmental deficits of Angelman syndrome in children if implemented prenatally or soon after birth.
